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  • Review Article
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Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs

Nature Reviews Cancer volume 2, pages 431–441 (2002)Cite this article

Key Points

  • Chemotherapeutic drugs are most toxic to rapidly proliferating cells in the gastrointestinal tract and the blood-forming haematopoietic system. As a result, the dosage of the chemotherapeutic agents must be reduced, along with the likelihood of tumour eradication.

  • Gene therapy approaches have been developed to promote stable integration of drug-resistance genes in pluripotent haematopoietic stem cells.

  • Protecting a cancer patient's haematopoietic stem cells from the toxic effects of cancer therapies involves autologous transplantation of genetically modified bone-marrow cells. These cells are transduced ex vivo with a retroviral vector that contains a drug-resistance gene before being transplanted back into the patient.

  • The choice of envelope protein expressed by the viral vector has proven to be an important determinant of stem-cell transduction efficiency, due to the fact that the receptors for viral envelopes are expressed at varying levels on the stem-cell surface.

  • Mouse oncoretroviruses can only gain access to nuclear chromatin during mitosis, whereas lentiviral vectors can enter an intact nucleus directly through the nuclear pores.

  • Various drug-resistance genes have been shown to protect haematopoietic stem cells in animal models. These include the multidrug resistance 1 gene (Mdr1), dihydrofolate reductase (Dhfr) and methylguanine methyltransferase (Mgmt).

  • Several clinical trials have evaluated the feasiblity of haematopoietic protection using MDR1-expressing vectors in adult cancer patients.

  • Haematopoietic stem-cell gene therapy offers an opportunity to widen the anticancer therapeutic index.

Abstract

One of the most important complications of cancer chemotherapy is the toxic effect that the drugs have on normal tissues — particularly the bone marrow. Several gene-therapy vectors have been developed with the aim of expressing drug-resistance genes specifically in bone-marrow stem cells, so protecting them from chemotherapeutics. The feasibility of this approach has been established in animal model systems, and recent advances in the design of gene-therapy vectors offer promise for future clinical applications.

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Figure 1: Gene therapy to protect haematopoietic cells from the toxic effects of chemotherapy.
Figure 2: Biological barriers to retroviral vector insertion into stem cells.
Figure 3: P-glycoprotein as a transmembrane drug efflux pump.
Figure 4: Folate metabolism and drug resistance.
Figure 5: Widening the therapeutic index vectors that express methylguanine methyltransferase and 6-BG.
Figure 6: In vivo stem-cell selection.

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Acknowledgements

I thank G. Hoskins for her expert editorial assistance in preparing this manuscript. This work was supported in part by the National Heart, Lung and Blood Institute Program Project, ASSISI Foundation of Memphis and the American Lebanese Syrian Associated Charities.

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Authors and Affiliations

  1. Department of Hematology/Oncology, Division of Experimental Hematology, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Brian P. Sorrentino

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DATABASES

Cancer.gov

brain tumours

breast cancer

Hodgkin's disease

paediatric acute lymphocytic leukaemia

testicular cancer

GenBank

feline leukaemia virus RD114 envelope

gibbon ape leukaemia virus envelope

HIV

lentiviral gag protein

vesicular stomatitis virus G protein

LocusLink

CD34

DHFR

fibronectin

granulocyte colony-stimulating factor

Mdr1

MDR1

MGMT

p27

Medscape DrugInfo

cyclophosphamide

doxorubicin

etoposide

methotrexate

paclitaxel

taxol

temozolomide

trimetrexate

vinblastine

OMIM

β-thalassaemia

chronic granulomatous disease

FURTHER INFORMATION

American Society of Gene Therapy

Food and Drug Administration site regarding Gene Therapy

Human ATP-Binding Cassette Transporters

National Heart, Lung, and Blood Institute Programs of Excellence in Gene Therapy

Recombinant DNA Advisory Committee site regarding Human Gene Therapy

Glossary

THERAPEUTIC INDEX

The difference in drug dose associated with a beneficial clinical response versus that causing undesirable side effects.

MYELOSUPPRESSION

Decreased production of blood cells due to toxic drug side effects. This can result in anaemia that requires red-blood-cell transfusion, increased susceptibility to infections due to low numbers of leukocytes and increased bleeding propensity due to insufficient numbers of platelets.

AUTOLOGOUS TRANSPLANTATION

Collection of a patient's own haematopoietic stem cells before high-dose chemotherapy, with subsequent re-administration of these cells after myelosuppressive treatments to allow for haematopoietic reconstitution and recovery.

TRANSDUCTION

The genetic modification of a cell using a viral vector. In the context of retroviral vectors, this means that the cell will have a stably integrated copy of the recombinant vector genome within the host-cell chromosome.

RETROVIRAL VECTOR

A disabled RNA virus in which the viral genes have been replaced with engineered sequences, such as drug-resistance genes. The vector particles can no longer replicate in cells, but can insert and express a therapeutic gene in appropriate target cells.

ONCORETROVIRUS

A class of simple retrovirus that is derived from mouse and avian viruses. These viruses lack expression of accessory proteins, and require cell division for stable integration into the target-cell genome.

PSEUDOTYPE

A specific characteristic of a retrovirus, determined by the envelope protein that is present on the surface of the viral particle. The choice of envelope protein will define the tropism for the virus, and affect the efficiency by which stem cells are transduced.

HUMAN FOAMY VIRUS

Retroviruses that belong to the Spumavirus family. Despite the name, these viruses are not pathogenic in humans, and have several unique properties that are useful for gene-therapy vectors.

LENTIVIRAL VECTOR

A vector that is based on retroviruses that infect human and primate species. These have a more complex genomic structure than oncoretroviruses, and express several accessory proteins in addition to gag, pol and env. The main advantage for gene therapy is their relatively increased efficiency for stably transducing quiescent cells.

CHROMATIN INSULATOR

A genetic element found in a wide variety of species that protects a gene from undesired cis-linked modulators of gene expression. Insulators are classically defined by their ability to block enhancer function, but they can also block elements that silence gene expression.

BICISTRONIC VECTOR

A vector that is designed to express two distinct genes simultaneously.

MYELOABLATIVE CONDITIONING

A treatment given to a patient before stem-cell transplantation that is designed to enhance engraftment of subsequently administered stem cells. These treatments, such as irradiation or high-dose chemotherapy, can be relatively toxic to the patient.

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Sorrentino, B. Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs. Nat Rev Cancer 2, 431–441 (2002). https://doi.org/10.1038/nrc823

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